T regulatory cells (Treg cells) are currently classified into two main subsets, according to their origin and suppressive activity (Bluestone, J. A. & Abbas, A. K. Natural versus adaptive regulatory T cells. Nature Rev. Immunol. 3, 253-257 (2003)). Natural Treg cells originate in the thymus by high-affinity interaction of the T-cell receptor (TCR) with antigens expressed in the thymic stroma. They have been classically described to suppress the proliferation of effector T cells in vitro in a contact-dependent, cytokine-independent manner. Natural Treg cells constitutively express CD25, cytotoxic T-lymphocyte antigen 4 (CTLA4), glucocorticoid-induced tumour necrosis factor (TNF) receptor (GITR) and OX40, molecules that characterize activated lymphocytes. However, the high-level expression of the transcription factor FOXP3 (forkhead box p3) is the most distinctive marker for the regulatory lineage, at least in the murine system. Although incompletely characterized to date, the network of natural Treg-cell suppression mechanisms includes surface molecules such as CTLA4, membrane-bound transforming growth factor (TGF) and the pericellular generation of adenosine.
Depletion of naturally occurring Treg cells in normal hosts results in various autoimmune diseases because the host immune system is unchecked and goes to attack the body's own tissue. In rodents, reduction or functional alteration of CD25+ CD4+ regulatory T cells has been shown to cause the spontaneous development of various organ-specific autoimmune diseases including thyroiditis, gastritis, and type I diabetes. Regulatory I cells are also critical for the controlled response to environmental antigens and have been shown to prevent inflammatory bowel disease (IBD) as well as allergy.
Treg have now been described in a large number of systems and have emerged as a major mechanism for the maintenance of self-tolerance and protection from autoimmune disease. Whereas Treg limit autoimmunity, they also attenuate the potency of anti-tumor and anti-viral immunity. For example, in the case of cancer, Treg cells may have a negative influence since they could hamper normally desirable antitumour immune responses and there is indeed already some evidence to suggest that cancer patients show increased numbers of active Treg cells specific for tumour proteins both in their blood and within the tumours themselves. Indeed several recent studies in human, reported elevated percentages of CD4+CD25+ Treg cells in a variety of cancers including lung cancer, breast cancer, ovarian cancer, melanoma, liver cancer, gastric cancer and lymphoma. In the case of viral infections, higher numbers of Treg cells have been reported in individuals who are chronically infected with hepatitis C and hepatitis B virus and in patients infected with human immunodeficiency virus.
Accordingly, methods and compositions for the inhibition or elimination of Treg activity would be useful in the treatment of diseases and disorders characterized by an increased Treg activity, e.g., cancer, infectious disease and immune response.
A recent study demonstrates that CD39 might represent a target for the development of novel therapeutic methods useful for treating diseases associated with Treg activity (Deaglio S, Dwyer K M, Gao W, Friedman D, Usheva A, Erat A, Chen J F, Enjyoji K, Linden J, Oukka M, Kuchroo V K, Strom T B, Robson S C. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007 Jun. 11; 204(6):1257-65. Epub 2007 May 14). The authors indeed showed that CD39 is a cell surface marker of Foxp3 Treg cells which may regulate immune T cell suppression by the downstream production of adenosine.